Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (nitrogen monoxide, NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells.
Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are extracellular arginine, 17β-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349) were able to obtain a marked increase in eNOS by means of exercise training and the increase in shear stress associated therewith.
Whether regulation at the post-transcriptional level is relevant in vivo, has not been unambiguously proven. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease.
On the other hand, the significance of the upregulation of the eNOS protein is scientifically accepted. Thus, there are findings which show that the protective properties of the HMG-CoA reductase inhibitor simvastatin can be attributed, besides to the lipid lowering, also in part to an increase in eNOS expression in vivo (Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880). It is additionally known that single point mutations in the 5′-flanking region of the eNOS gene (“eNOS promoter”), and the reduction in the rate of eNOS gene transcription associated therewith, in the Japanese population is associated with an increase in the risk of coronary spasms (Nakayama et al., Circulation 99 (1999) 2864).
The current assumption therefore is that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in very early stages of a wide variety of cardiovascular disorders it is possible for a dysfunction of this type in the endothelium lining the blood vessels to lead to a deficiency of bioactive NO, which is manifested as the disorder progresses in the form of measurable pathophysiological and morphological changes. Thus, critical steps in early atherogenesis are speeded up by a decrease in endothelial NO release, such as, for example, the oxidation of low density lipoproteins, the recruitment and deposition of monocytes in the intima of vessels, and the proliferation of intimal cells. A consequence of atherogenesis is the formation of plaques on the inside of the blood vessels, which may in turn lead, through a diminution in the shear stress, to a further decrease in endothelial NO release and a further deterioration in the pathology. Since endothelial NO is also a vasodilator, a decrease thereof frequently also leads to hypertension which may, as an independent risk factor, cause further organ damage.
The aim of a therapeutic approach to the treatment of these disorders must accordingly be to interrupt this chain of events by increasing the endothelial NO expression. Gene transfer experiments which lead in vitro to overexpression of NO synthase in previously damaged vessels are in fact able to counteract the described processes and are thus evidence of the correctness of this approach (Varenne et al., Hum. Gene Ther. 11 (2000) 1329).
Some low molecular weight compounds which, in cell cultures, may lead to a direct effect on eNOS transcription and expression are disclosed in the literature. For the statins, as has already been mentioned, it has been possible to show such an increase in eNOS in vivo as a side effect. In view of the known range of side effects of this class of substances, however, it is unclear how far use of this effect can be made in a toxicologically unproblematic dose. Liao et al. claim in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents which influence the organization of the actin cytoskeleton for increasing eNOS in endothelial cells and for the therapy of various disorders such as, for example, strokes or pulmonary hypertension without, however, indicating a specific way of achieving this. Certain amide derivatives which upregulate the expression of endothelial NO synthase, in particular N-cycloalkyl amides in which the cycloalkyl ring is fused to a benzene ring or a heteroaromatic ring, have been described in WO 02/064146, WO 02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372 and WO 2004/014842. Certain triaza- and tetraaza-anthracenedione derivatives which upregulate the expression of endothelial NO synthase have been described in WO 2004/094425. There still exists a need for further compounds which upregulate the expression of endothelial NO synthase and have a favorable property profile and are useful as pharmaceuticals for the treatment of various diseases such as atherosclerosis, coronary artery disease or cardiac insufficiency, for example. Surprisingly it has now been found that the compounds of the formula I are modulators of the transcription of endothelial NO synthase and in particular stimulate, or upregulate, the expression of eNOS, and are useful for the treatment of various diseases such as the mentioned cardiovascular disorders.
Certain heteroaryl-substituted carboxamides, in which an aryl or heteroaryl group is linked to the heteroaryl substituent and which are structurally related to formula I, have already been described. For example, in EP 0382199 and EP 0440183 oxazole compounds are described which are useful for the treatment of diabetes and metabolic disorders and the definition of which comprises, among others, 3-(oxazol-2-yl)-propionamides and 4-(oxazol-2-yl)-butyramides which carry an optionally substituted phenyl group in the 4-position of the oxazole ring and optionally an alkyl group in the 5-position of the oxazole ring. In EP 0432740 anti-inflammatory 2-substituted thiazole derivatives are described which are characterized by a 3-alkyl-5-tert-butyl-4-hydroxyphenyl substituent in the 4-position and in which the substituent in the 2-position can be, among others, a carboxamide group which is linked to the thiazole ring by an alkanediyl group the chain of which can optionally contain an oxygen atom, a sulfur atom or a carbonyl group. In EP 0018497 and U.S. Pat. No. 4,645,525 herbicidal 2-azolyloxy-acetamides and 2-alkyl-2-azolyloxy-acetamides are described in which the 5-membered azole ring comprises at least one nitrogen ring member and one ring member chosen from oxygen and sulfur and can be substituted by various substituents including optionally substituted aryl, arylalkyl-, aryloxy, arylthio, for example. Certain imidazol-2-yl compounds, which are inhibitors of acyl CoA cholesterol acyl transferase useful for the treatment of hypercholesterolemia and atherosclerosis and which in particular are substituted by two phenyl groups in positions 4 and 5 of the imidazole ring, are described in EP 0372445 and U.S. Pat. No. 5,358,946. Some 3-(4,5-diphenyl-imidazol-2-ylthio)-propionamides are also described in Ali et al., J. Prakt. Chem. 316 (1974) 147. Certain thiazol-2-yl compounds, which have 5-lipoxygenase inhibitory and antithrombotic activity and are substituted by two phenyl groups in positions 4 and 5 of the thiazole ring, such as 4,5-disubstituted 2-(ureidomethyl)-thiazoles, are described in EP 0388909. In EP 0417751 2-guanidino -thiazol-4-yl-substituted thiazoles and pyridines are described which are H2 receptor antagonists useful for the treatment of ulcers and which can contain, among other groups, a urea moiety which is linked to the thiazole or pyridine ring by an alkanediyl group. In WO 96/16040 and US 2003/0018025, which relate to brain dopamine agonistic and antagonistic imidazolylalkylamine derivatives, certain 1-(2-(4-phenylimidazol-4(5)-yl)propanoyl)-piperazines and -piperidines are described as intermediates which comprise a phenyl or heteroaryl group in the piperazine group and the piperidine group and which can be reduced to the respective imidazolylalkylamine derivatives. The generic definition of the compounds in WO 00/45635, which relates to antimicrobial thiazole derivatives and combinatorial libraries thereof, comprises 2-(thiazol-2-ylamino)acetamides in which the thiazole ring can carry phenyl and heteroaryl substituents. Certain cannabinoid CB1 receptor antagonistic thiophen-2-ylmethylamine derivatives in which the amino group can be part of a urea moiety, which carry in positions 4 and 5 of the thiophene ring two optionally substituted phenyl groups and therefore are not comprised by the definition of the compounds of the present invention, are described in WO 2006/084975. Some further specific heteroaryl-substituted carboxamides in which an optionally substituted phenyl group is linked to the heteroaryl substituent which is a 5-membered pyrrolyl, imidazolyl or thiazolyl group, are known, such as the compound N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide, for example, which may also be named as N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylthio)-acetamide or in its tautomeric form as N-(4-chloro-phenyl)-2-(5-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide and which is described in Ivanova et al., Chemistry of Heterocyclic Compounds 41 (2005) 761. A stimulating effect of known heteroaryl-substituted carboxamides on the transcription or the expression of eNOS and their use in the treatment of diseases which is based on such effect, has not been described.